Olivetol-cyclodextrin complexes and regio-selective process for preparing delta 9-tetrahydrocannabinol

ABSTRACT

A cyclodextrin-olivetol derivative complex is provided. The complex effectively blocks reaction at specific carbons to prevent unwanted reactions. A process for preparing a cannabinoid compound is further provided. The process comprises reacting at least one terpenoid with cyclodextrin-olivetol derivative complex to produce the cannabinoid compound.

FIELD OF THE INVENTION

The present invention relates to the regio-selective synthesis ofΔ⁹-hydrodannabinol (THC) and THC derivatives, and more particularly tothe condensation reaction of a terpinoid with olivetol and olivetolderivatives using cyclodextrins as space blockers for theregio-selective synthesis of THC.

BACKGROUND OF THE INVENTION

Naturally occurring cannabinoids are the biologically active componentsof cannabis. Pharmaceutical interest in cannabinoids has increased dueto FDA approval of Δ⁹-tetrahydrocannabinol (THC) for several therapeuticapplications

In the 1940's A. R. Todd and R. Adams attempted to prepare severalsynthetic analogs that were shown to have similar activity of marijuanaeven before the structure of THC was firmly established. Many effortshave been made to develop an efficient strategy to prepare the THC.Among the several approaches to synthesize THC and its derivatives, thecondensation of olivetol with several terpene based compounds, such as(−)-verbenol, (+)-chrysanthanol, (+)-p-mentha-2,8-diene-2-ol,(+)-trans-2-carene epoxide, (+)-3-carene oxide and(+)-p-mentha-2-ene-1,8-diol are more efficient than other approaches,such as Diels-Alder reaction of cinnamic acid derivatives, reaction ofcitral and lithium derivatives of the olivetol and olivetol dimethylether and synthetic route to the THC based on the Pechmann condensationreaction. All known synthesis paths share a common drawback—the finalproduct is a resinous, hard to purify, complex mixture containing up toeight major isomers. As a result, multiple purification steps are oftenrequired to purify the THC from the reaction mixture when thosesynthetic approaches are adopted. Production of THC and THC derivativesis therefor costly to scale up for commercial purposes.

SUMMARY OF THE INVENTION

An aspect of the present invention is to provide a compositioncomprising olivetol or an olivetol derivative complexed with at leastone cyclodextrin to block unwanted reactions.

Another aspect of the present invention is to provide a process forpreparing a cannabinoid compound comprising complexing olivetol or anolivetol derivative with at least one cyclodextrin; and reacting atleast one terpenoid with the complexed olivetol to produce thecannabinoid compound.

These are merely illustrative aspects of the present invention andshould not be deemed an all-inclusive listing of the innumerable aspectsassociated with the present invention. These and other aspects willbecome apparent to those skilled in the art in light of the followingdisclosure.

DETAILED DESCRIPTION

A cyclodextrin-olivetol derivative complex is disclosed herein.Cyclodextrins are cyclic oligosaccharides having at least sixglucopyranose units. Commercially available cyclodextrins typically have6, 7 and 8 glucopyranose units. Cyclodextrins are shaped as a torus,with a hydrophilic outer surface and a hydrophobic inner surface.Cyclodextrins are capable of forming inclusion complexes withhydrophobic guest molecules of suitable diameters. These cyclodextrincomplexes encapsulate guest molecules.

In the present invention, the cyclodextrin provides its cavity as anon-polar sterically hindered reaction field, in which the olivetolderivative is complexed. In the description below, the term “olivetolderivative: is deemed to include olivetol. The cyclodextrin-olivetolderivative complex is illustrated below.

wherein R₁ and R₂ are H or an alkyl group; and wherein R₃ is an akylhaving 1 to about 10 carbons, branched or unbranched or an aryl(non-polar). When R₁ and R₂ are H and R₃ is a pentyl group, the compoundis olivetol.

In the resulting complex, the C₃ and C₅ positions of the olivetolderivative are blocked, thereby preventing unwanted reactions at thesecarbons. The C₁ carbon is left unprotected and is available forreaction.

Conventional synthesis of cannabinoids from olivetol derivativesrequires a condensation reaction of a substrate with the olivetolderivative at C₁. Reactions at C₃ and C₅ result in unwanted by-productsthat decrease yield and are difficult to remove.

As a result of the complexation of an olivetol derivative withcyclodextrin, the side reaction pathways related to reactions at the C₃and C₅ positions have been successfully blocked.

The composition of the cyclodextrin and olivetol derivative non-covalentcomplex is prepared as an intermediate, which may or may not need to beisolated for further reaction to prepare THC.

The reaction may be carried out in a one or two-step process. For thetwo-step reaction process, the cyclodextrin-olivetol derivative complexis isolated, and then converted to the desired product at a later time.

The selection of a suitable cyclodextrin depends primarily on the sizingof the non-polar cavity. Cyclodextrins suitable for complexation witholivetol derivatives include but are not limited to naturalα-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or modified syntheticcyclodextrin, such as (2-hydroxy-propyl)-β-cyclodextrin,(2-carboxyethyl)-α,β,γ-cyclodextrin, (2,6-Di-O)-ethyl-β-cyclodextrin and(2-hydroxy-ethyl)-β-cyclodextrin.

The cyclodextrin-olivetol derivative complex is formed by mixing thecyclodextrin and olivetol derivative in a suitable solvent. Suitablesolvents include but are not limited to tetrahydrofuran,dimethyl-formaldehyde, hydrocarbons, halogenated hydrocarbons, etherssuch as diethyl ether, ketones such as acetone and methyl ethyl ketone,alcohols such as methanol, ethanol and isopropyl alcohol and mixturesthereof. Preferred solvents include halogenated hydrocarbons,tetrahydrofuran and dimethyl formaldehyde. The reaction is preferably atroom temperature for about 30 minutes, although time and temperature arenot critical. The solvent is then evaporated at reduced pressure,leaving a solid cyclodextrin-olivetol derivative complex.

The reaction of the cyclodextrin-olivetol derivative complex isillustrated below:

To prepare THC cannabinoids, the substrates used in this reactioninclude (−)-verbenol, (+)-chrysanthanol, (+)-p-mentha-2,8-diene-2-ol,(+)-trans-2-carene epoxide, (+)-3-carene oxide and(+)-p-mentha-2-ene-1,8-diol. These substrates are illustrative and arenot meant to be limiting of the present invention.

The preparation of a THC derivative from an olivetol derivative is wellknown in the art. The process includes dissolving thecyclodextrin-olivetol derivative complex in a solvent system as definedabove. While maintaining a reduced temperature, the substrate and anacid catalyst, including but not limited to Lewis acids, are added tothe cyclodextrin-olivetol derivative complex. The temperature istypically maintained at about 0° C. to about 15° C., with about 5° C.being preferred. The reaction process may be monitored with HPLC, andupon completion of the reaction the reaction may be quenched with abase. The resulting mixture is purified by conventional methods known inthe art.

In addition, the above reaction may be altered to result in theformation of a cannabidiol, typically by using a weaker acid catalyst orby reducing the temperature of the reaction, as is well known in theart. The cannabidiol can then be converted to a cannabinoid compound orutilized as an intermediate for a different reaction.

Futhermore, the presence of ABN-cannabidiol has been detected in thereaction mixture, the ABN-cannabidiol being the result of eitherreaction of the (+)-2,8-menthadiene-1-ol at the C₃ or C₅ position due toincomplete complexation of the cyclodextrin/olivetol, or the result ofrearrangement of the normal cannabidiol. In either case, it has beendetermined the ABN-cannabidiol, in the presence of at least onecylcodextrin and at least one Lewis acid, rearranges to normalcannabidiol.

The following examples are offered to illustrate aspects of the presentinvention, and are not intended to limit or define the present inventionin any manner

EXAMPLES Example 1 The preparation of5-pentyl-1,3-benzenediol/cyclodextrin complex

5 g of olivetol and 31 g of β-cyclodextrin were mixed in 500 mltetrahedronfuran and stirred at 25° C. for about 30 minutes. The solventwas evaporated at reduced pressure. A white solid of the5-pentyl-1,3-benzenediol/cyclodextrin complex, about 36 g, was obtained.

Example 2 Preparation of(−)-2-(p-mentha-2,8-diene-3-yl)pentylbenzene-1,3-diol

The freshly prepared olivetol/cyclodextrin complex of Example 1 and 9 gof MgSO₄ were mixed together and stirred in 500 ml of tetrahedronfuran.The reaction mixture was cooled in an ice water bath to keep thetemperature at about 5° C. 4.4 g of (+)-2,8-menthadiene-1-ol was placedin an addition funnel and p-TSA acid was placed into a syringe. The(+)-2,8-menthadiene-1-ol and the acid catalyst were added to thereaction mixture drop wise over 15 minutes. The reaction progress wasmonitored by HPLC and, upon completion of the reaction, an excess ofNaHCO₃ was added to quench the reaction.

Salts were filtered out from the reaction mixture and the organicsolvent was evaporated, leaving about 7.5 g of an oil. The oil wasdissolved into 100 ml of petroleum ether and was washed with 300 ml ofwater twice and brine solution once. The product mixture was purifiedvia chromatography on a silica gel column utilizing heptane/acetonitrile(98:2) as the mobile phase. A fraction contained the (−)-cannabidiol,also known as (−)-2-(p-mentha-2,8-diene-3yl)pentylbenzene-1,3-diol,which was concentrated to give an oil.

¹H NMR δH (300 MHz, CHCl3): 0.89 (3H,t), 1.27 (4H, m), 1.56 (2H,m), 1.65(3H,s), 1.79 (3H,s), 2.11 (2H,m), 2.44 (3H, m), 3.85 (1H,d), 4.6 (2H,d),5.58 (1H,s), 6.22 (2H,s). ¹³C NMR δH (300 mHz, CHCl3): 14.6, 20.8, 23.3,24.3, 28.7, 30.8, 37.4, 45.6, 108.2, 110.0, 111.4, 111.6, 124.2, 140.7,143.5, 145.4, 156.3.

Example 3 Preparation of (−)-trans-Δ⁹-tetrahydrocannabinol

The freshly prepared olivetol/cyclodextrin complex of Example 1 and 9 gof MgSO₄ were mixed together in 500 ml of tetrahydrofuran. The reactionmixture was cooled in an ice water bath to keep the temperature at about5° C. 4.4 g of (+)-2,8-menthadiene-1-ol was placed in an addition funneland BF₃Et₂O acid was placed into a syringe. The (+)-2,8-menthadiene-1-oland the acid catalyst were added to the reaction mixture drop wise over15 minutes. The reaction progress was monitored by HPLC and, uponcompletion of the reaction, an excess of NaHCO₃ was added to quench thereaction. Salts were filtered out from the reaction mixture and theorganic solvent was evaporated to give an oil. Approximately 7.0 g ofthe oil was obtained as a mixture of (−)-trans-Δ⁹-tetrahydrocannabinoland some minor amount of (−)-trans-Δ⁸-tetrahydrocannabinol. The oil wasdissolved into 100 ml of petroleum ether and was washed with 300 ml ofwater twice and brine solution once. The product mixture was purifiedvia chromatography on a silica gel column and(−)-trans-Δ⁹-tetrahydrocannabinol eluted with heptane/acetonitrile(98:2) as mobile phase. A fraction containing the(−)-trans-Δ⁹-tetrahydrocannabinol, with purity over 98%, wasconcentrated to give a light yellow oil.

Having described the invention in detail, those skilled in the art willappreciate that modifications may be made of the invention withoutdeparting from its spirit and scope. Therefore, it is not intended thatthe scope of the invention be limited to the specific embodimentsdescribed. Rather, it is intended that the appended claims and theirequivalents determine the scope of the invention.

1. A composition comprising an olivetol derivative complexed with atleast one cyclodextrin.
 2. The composition according to claim 1 whereinthe at least one cyclodextrin includes a cyclodextrin selected from thegroup consisting of natural α-cyclodextrin, β-cyclodextrin,γ-cyclodextrin or modified synthetic cyclodextrin, such as(2-hydroxy-propyl)-β-cyclodextrin, (2-carboxyethyl)-α,β,γ-cyclodextrin,(2,6-Di-O)-ethyl-β-cyclodextrin and (2-hydroxy-ethyl)-β-cyclodextrin. 3.The composition according to claim 1 wherein the olivetol derivativecomprises

wherein R₁ and R₂ are H or an alkyl or alcohol; and wherein R₃ isselected from the group consisting of normal akyl groups having 1 toabout 10 carbons, branched alkyl groups having 1 to about 10 carbons andaryl groups.
 4. The composition according to claim 1 wherein theolivetol derivative is olivetol.
 5. (canceled)
 6. A process forpreparing a cannabinoid compound comprising: complexing an olivetolderivative with at least one cyclodextrin; and reacting at least oneterpenoid with the complexed olivetol derivative to produce thecannabinoid compound.
 7. The process according to claim 6 wherein the atleast one cyclodextrin includes a cyclodextrin selected from the groupconsisting of natural α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin ormodified synthetic cyclodextrin, such as(2-hydroxy-propyl)-β-cyclodextrin, (2-carboxyethyl)-α,β,γ-cyclodextrin,(2,6-Di-O)-ethyl-β-cyclodextrin and (2-hydroxy-ethyl)-β-cyclodextrin. 8.The process according to claim 6 wherein the at least one terpenoid isselected from the group consisting of (−)-verbenol, (+)-chrysanthanol,(+)-p-mentha-2,8-diene-2-ol, (+)-trans-2-carene epoxide, (+)-3-careneoxide and (+)-p-mentha-2-ene-1,8-diol.
 9. The process according to claim6 further including maintaining a temperature below room temperaturewhile reacting the at least one terpenoid with the complexed olivetolderivative.
 10. The process according to claim 9 wherein the temperatureis about 0° C. to about 15° C.
 11. The process according to claim 6further including adding at least one acid catalyst.
 12. The processaccording to claim 6 further including quenching the reaction of the atleast one terpenoid with the complexed olivetol derivative with a base.13. The process according to claim 6 wherein the cannabinoid is anaturally occurring component of cannabis.
 14. The process according toclaim 6 wherein the cannabinoid is a synthetic analog of cannabis.
 15. Aprocess for preparing a cannabidiol compound comprising: complexing anolivetol derivative with at least one cyclodextrin; and reacting atleast one terpenoid with the complexed olivetol derivative at atemperature low enough to result in the production of a cannabidiolcompound.
 16. The process according to claim 15 wherein the at least onecyclodextrin includes a cyclodextrin selected from the group consistingof natural α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or modifiedsynthetic cyclodextrin, such as (2-hydroxy-propyl)-β-cyclodextrin,(2-carboxyethyl)-α,β,γ-cyclodextrin, (2,6-Di-O)-ethyl-β-cyclodextrin and(2-hydroxy-ethyl)-β-cyclodextrin.
 17. The process according to claim 15wherein the at least one terpenoid is selected from the group consistingof (−)-verbenol, (+)-chrysanthanol, (+)-p-mentha-2,8-diene-2-ol,(+)-trans-2-carene epoxide, (+)-3-carene oxide and(+)-p-mentha-2-ene-1,8-diol.
 18. The process according to claim 15further including adding at least one acid catalyst while reacting theat least one terpenoid with the complexed olivetol derivative, whereinthe acid catalyst is selected to result in the formation of thecannabidiol.
 19. The process according to claim 15 further includingquenching the reaction of the at least one terpenoid with the complexedolivetol derivative with a base.
 20. A process for preparingΔ⁹-tetrahydrocannabinol comprising: complexing olivetol with at leastone cyclodextrin; and reacting the complexed olivetol with(+)-p-mentha-2,8-diene-1-ol to form Δ⁹-tetrahydrocannabinol.
 21. Theprocess according to claim 20 wherein the at least one cyclodextrinincludes a cyclodextrin selected from the group consisting of naturalα-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or modified syntheticcyclodextrin, such as (2-hydroxy-propyl)-β-cyclodextrin,(2-carboxyethyl)-α,β,γ-cyclodextrin, (2,6-Di-O)-ethyl-β-cyclodextrin and(2-hydroxy-ethyl)-β-cyclodextrin.
 22. The process according to claim 20further including maintaining a temperature below room temperature whilereacting the (+)-p-mentha-2,8-diene-1-ol with the complexed olivetol.23. The process according to claim 20 wherein the temperature is about0° C. to about 15° C.
 24. The process according to claim 20 furtherincluding adding at least one acid catalyst while reacting the(+)-p-mentha-2,8-diene-1-ol with the complexed olivetol.
 25. The processaccording to claim 20 further including quenching with the reaction ofthe (+)-p-mentha-2,8-diene-1-ol with the complexed olivetol with a base.26-30. (canceled)